The build-up of stock of stable integrated proviruses overtime explains the difficulty in reducing HIV-1 DNA levels when treatment is initiated at the chronic stage of the infection.

Background: Understanding factors affecting the size and the evolution of the HIV reservoir is essential for the development of curative strategies. This study aimed to assess the impact of antiretroviral therapy (ART) initiated during primary infection (PHI) vs chronic infection (CHI) on the levels and dynamics of integrated HIV-1 DNA, a biomarker of viral persistence. Methods: Integrated and total HIV-1-DNA were measured in the blood of 92 patients treated during PHI (early group) and 41 during CHI (deferred group), at diagnosis, ART initiation, and 12-24 months on treatment. Results: On ART, detectable (>1.78 log10 copies/106 PBMCs) integrated HIV-1 DNA levels were significantly lower in the early vs deferred group (2.99 log10vs 3.29 log10,p = 0.005). The proportion of undetectable integrated HIV-1 DNA tended to be higher in the early group vs deferred group (61 % vs 46 %; p = 0.133). Conclusion: Treatment initiated at PHI limits the levels of integrated HIV-1 DNA in blood. However, initiating treatment at CHI does not allow reaching such low levels in most patients, probably because the stable proviruses at that stage are present in the less prone to elimination long-lived cells. Thus, early ART could provide an opportunity to preparing for functional cure and eradication strategies.

Once-daily dolutegravir versus darunavir plus cobicistat in adults at the time of primary HIV-1 infection: the OPTIPRIM2-ANRS 169 randomized, open-label, Phase 3 trial.

BACKGROUND: Whether integrase strand transfer inhibitors (INSTIs) can decrease HIV-1 DNA levels more rapidly than boosted PIs during primary HIV-1 infection (PHI) is unknown. We hypothesized that once-daily dolutegravir/tenofovir/emtricitabine could reduce the viral reservoir through rapid viral replication control further than once-daily darunavir/cobicistat/tenofovir/emtricitabine. METHODS: The OPTIPRIM2-ANRS 169 study was a randomized (1:1), open-label, multicentre trial in adults with ≤5 or ≤3 HIV antibodies detected, respectively, by western blot or immunoblot in the last 10 days. The primary endpoint was total HIV-1 DNA levels in PBMCs at Week 48 (W48) adjusted for baseline levels. The main secondary endpoint was HIV-1 RNA level decrease. RESULTS: Between April 2017 and August 2018, 101 patients were included from 31 hospitals. Most patients were men (93%), the median age was 36 years and 17% were Fiebig stage ≤3. The median (IQR) plasma HIV-1 RNA and DNA levels were, respectively, 5.8 (5.0-6.6) and 3.87 (3.52-4.15) log10 copies/million PBMCs. The median (IQR) decreases in HIV-1 DNA levels at W48 were -1.48 (-1.74 to -1.06) and -1.39 (-1.55 to -0.98) log10 copies/million PBMCs in the dolutegravir and darunavir/cobicistat groups, respectively (P = 0.52). Plasma HIV-1 RNA levels were <50 copies/mL in 24% versus 0% of patients in the dolutegravir and darunavir/cobicistat groups at W4, 55% versus 2% at W8, 67% versus 17% at W12, and 94% versus 90% at W48, respectively. CONCLUSIONS: Dolutegravir-based and darunavir-based regimens initiated during PHI strongly and similarly decreased the blood reservoir size. Considering the rapid viral suppression during a period of high HIV-1 transmission risk, dolutegravir-based regimens are a major first-line option.

HIV-1-RNA and total HIV-1-DNA loads in the genital compartment in men receiving dolutegravir- versus darunavir-based combined ART (cART) regimens during primary HIV infection.

BACKGROUND: Dolutegravir is a widespread integrase strand-transfer inhibitor (INSTI) recommended for treatment of primary HIV infection (PHI). PHI is a high-risk stage for sexual transmission because of the high viral load in semen. Yet dolutegravir concentrations in semen are lower than in blood during chronic treatment. OBJECTIVES: To compare the kinetics of HIV-RNA and total HIV-DNA in the genital compartment in subjects receiving either tenofovir/emtricitabine/dolutegravir or tenofovir/emtricitabine/darunavir/cobicistat as a first-line combined ART (cART) at the time of PHI. PATIENTS AND METHODS: Eighteen subjects receiving tenofovir/emtricitabine/dolutegravir and 19 receiving tenofovir/emtricitabine/darunavir/cobicistat enrolled in the ANRS169 OPTIPRIM-2 trial participated in the genital substudy. RESULTS: Between week (W) 0 and W2 HIV-RNA in seminal plasma (SP) decreased by 1 log10 copies/mL. Undetectable SP HIV-RNA was achieved in similar proportions between the two regimens at each timepoint. Overall, eight patients still presented detectable HIV-RNA or HIV-DNA in semen at W48; 15.4% and 28.6% presented detectable HIV-RNA and 9.1% and 14.3% presented detectable HIV-DNA in dolutegravir- and darunavir-based cART groups, respectively, with no significant difference. CONCLUSIONS: For the first time, to the best of our knowledge, we showed that a dolutegravir-based regimen initiated as soon as PHI reduces HIV-RNA and HIV-DNA with no difference compared with a control group receiving a darunavir-based regimen. Although the viral purge in semen seems longer after treatment in PHI than CHI, due to high viral loads, early dolutegravir-based treatment initiation permits a major decay of both viral particles and infected cells in semen, efficiently reducing the high risk of transmission during PHI.

Immunogenicity and safety of yellow fever vaccine in HIV-1-infected patients.

OBJECTIVES: The objective of this study is to investigate immunogenicity and safety of the yellow fever vaccine (YFV) in HIV-infected (HIV+) patients with high CD4 T-cell counts. DESIGN: In this prospective, comparative study of YFV-naive adults: 40 HIV+ under antiretroviral therapy (ART) with CD4 T-cell count above 350 cells/µl and plasma HIV-RNA less than 50 copies/ml for at least 6 months and 31 HIV-negative (HIV-) received one injection of the YF-17D strain vaccine. METHODS: Serologic response was assessed by using a plaque reduction neutralizing test and YFV-specific T cells by using an INFγ-Elispot assay. RESULTS: YFV was well tolerated in both groups. Most participants had asymptomatic YFV viremia at day (D) 7 after vaccination (77% of HIV- and 82% of HIV+, P = 0.58), with higher plasma level of YFV RNA in HIV+ than in HIV- (median 2.46 log10 copies/ml (range: 1.15-4.16) and 1.91 log10 copies/ml (1.15-3.19), respectively, P = 0.011). A significant but transient decrease in CD4 cell counts was seen at D7 in both groups, more pronounced in HIV- than in HIV+ patients (-261.5 versus -111.5 cells/µl, respectively, P = 0.0003), but no HIV breakthrough was observed in plasma. All participants developed protective neutralizing antibody levels from D28 and up to 1 year after injection. At D91, fewer HIV+ than HIV- participants exhibited YFV T-cell response (20 versus 54%, respectively, P = 0.037). CONCLUSION: At 1 year, YFV was immunogenic and well tolerated in HIV-infected adults under ART with CD4 T-cell counts above 350 cells/µl. However, a lower immunity of YFV T cells in HIV-infected patients was observed as compared with HIV- participants. CLINICAL TRIALS REGISTRATION: NCT01426243.

Screening test for neutralizing antibodies against yellow fever virus, based on a flavivirus pseudotype.

Given the possibility of yellow fever virus reintroduction in epidemiologically receptive geographic areas, the risk of vaccine supply disruption is a serious issue. New strategies to reduce the doses of injected vaccines should be evaluated very carefully in terms of immunogenicity. The plaque reduction test for the determination of neutralizing antibodies (PRNT) is particularly time-consuming and requires the use of a confinement laboratory. We have developed a new test based on the use of a non-infectious pseudovirus (WN/YF17D). The presence of a reporter gene allows sensitive determination of neutralizing antibodies by flow cytometry. This WN/YF17D test was as sensitive as PRNT for the follow-up of yellow fever vaccinees. Both tests lacked specificity with sera from patients hospitalized for acute Dengue virus infection. Conversely, both assays were strictly negative in adults never exposed to flavivirus infection or vaccination, and in patients sampled some time after acute Dengue infection. This WN/YF17D test will be particularly useful for large epidemiological studies and for screening for neutralizing antibodies against yellow fever virus.

Effect of two injections of non-adjuvanted influenza A H1N1pdm2009 vaccine in renal transplant recipients: INSERM C09-32 TRANSFLUVAC trial.

BACKGROUND: Enhancing vaccine immunogenicity in kidney transplant recipients, particularly against influenza, is required since the immunosuppression used to prevent graft rejection limits vaccine immunogenicity. We therefore investigated the immunogenicity and safety of a double dose non-adjuvanted vaccination regimen against influenza H1N1pdm2009 in kidney transplant adult recipients. METHODS: A prospective single-arm study was conducted including 121 renal transplant recipients under triple immunosuppressive regimen. Patients received 2 injections (day 0, day 21) of an inactivated, non-adjuvanted H1N1pdm2009 vaccine. Immunogenicity (hemagglutination-inhibition [HI] antibodies and anti-hemagglutin [HA] specific T cells) was evaluated after one and two injections (day 21, day 42) and at 6 months (day 182). RESULTS: The seroprotection rate (HI antibody titer≥1/40) was 19% at day 0 (n=119), 53% at day 21 (n=118), 60% at day 42 (n=116) (p=0.013; day 42 vs. day 21) and 56% at day 182 (n=113). The seroconversion rate was 24% and 32%, the geometric mean fold rise was 3.7 and 4.6 after the first and second injections, respectively. T-cell immunity to the H1N1pdm2009 vaccine showed a two-fold increase from baseline, though not statistically significant, in H1N1pdm2009-HA-specific CD4+ and CD8+ T cells in 34% and 48% of cases, respectively. No rejection episodes related to vaccination were observed while the donor-specific antibodies and creatinine clearance remained unchanged throughout the study. CONCLUSION: Administration of two doses of the non-adjuvanted influenza H1N1pdm2009 vaccine in renal transplant patients is safe and induces a significant seroprotection, not strong enough yet to meet European or US requirements for adults below 60 years, but comparable to seroprotection levels usually observed in the non immunosuppressed elderly population or conferred by a single dose of adjuvanted vaccine in solid organ transplant recipients. These results provide useful indications for future strategies required to improve immunogenicity of vaccines against influenza in transplanted patients.

Incidence and risk factors of thrombocytopenia in patients receiving intermittent antiretroviral therapy: a substudy of the ANRS 106-window trial.

BACKGROUND: Incidence and risk factors for thrombocytopenia in patients discontinuing highly active antiretroviral therapy (HAART) have not been fully investigated. METHODS: Well-suppressed patients on HAART were randomized to continuous (CT) or intermittent therapy (IT) for 96 weeks. Incidence of thrombocytopenia (<150 x 10(3) platelets/mm(3)) was assessed and multivariate analysis performed to identify baseline predictors. Correlations were assessed between platelet, CD4, CD8 T-cell counts, and viral load after treatment interruption. RESULTS: Three hundred ninety-one patients were included, with a median baseline platelet count of 243,000/mm(3). The incidence of thrombocytopenia at week 96 was significantly higher in the IT versus the CT arm (25.4% versus 9.8%, respectively, P < 0.001) and median time to thrombocytopenia was 9 weeks. In multivariate analysis, the IT strategy: odds ratio (OR) = 4.1 (2.1-7.9; P < 0.0001), a history of thrombocytopenia: OR = 11.9 (2.4-57.9; P = 0.002), and a low baseline platelet count: OR = 3.4 (2.3-5.1; P < 0.0001) were associated with an increased risk of thrombocytopenia. Also, after treatment interruption, changes from baseline in platelet counts were correlated with changes in CD4 T-cell counts and plasma HIV RNA levels (P < 0.001 for both). CONCLUSIONS: Intermittent therapy is associated with a high incidence of thrombocytopenia, especially among patients with low platelet counts and a history of thrombocytopenia.

Interruption of antiretroviral therapy initiated during primary HIV-1 infection: impact of a therapeutic vaccination strategy combined with interleukin (IL)-2 compared with IL-2 alone in the ANRS 095 Randomized Study.

HIV-specific T cell responses play a critical role in the control of infection. We evaluated the impact of immune-based interventions in patients first treated during primary HIV-1 infection (PHI). Forty-three patients were randomized within three groups, to receive either interleukin-2 (IL-2 group), or boosts of ALVAC-HIV (vCP1433) and LIPO-6T followed by interleukin-2 (Vac-IL2 group), compared with no immune intervention (control group), and were monitored for T cell responses. Impact of strategies on viral replication was subsequently assessed during long-term treatment interruption. HIV-specific CD4(+) T cell responses did not change during the study period in immunized patients relative to controls, and vaccination had only a transient effect on interferon-gamma-producing CD8 responses. Viral rebound after treatment interruption was similar in immunized patients and controls. Forty percent of patients had HIV RNA values <10,000 copies/ml 12 weeks after interruption. The cumulative time off treatment represented almost half the total follow-up period. Immunological and virological status during PHI and HIV DNA load at interruption were predictive of the level of viral rebound after treatment interruption, whereas HIV RNA level during PHI and HIV DNA level at interruption were predictive of the time off treatment. Treatment interruption is safe in patients treated early after primary HIV infection. On the basis of this pilot study, HIV immunizations and interleukin-2 appear to have no supplementary benefit.

Clinical safety of HIV lipopeptides used as vaccines in healthy volunteers and HIV-infected adults.

BACKGROUND: HIV-1 lipopeptides have been developed by the French National Agency for AIDS Research (ANRS) for use as candidate vaccine against HIV since 1994. Between 1996 and 2005, four different lipopeptide constructs were tested alone or in combination with recombinant canarypox HIV vaccines in 10 trials conducted in France. The aim of this study was to review clinical safety of HIV lipopeptides. METHODS: A meta-analysis based on individual subject data examined clinical safety data collected in eight preventive trials and two therapeutic trials enrolling 200 HIV-1-uninfected healthy volunteers and 48 HIV-1-infected patients. RESULTS: Of 248 trial participants, eight (3.2%) did not complete follow-up: seven among the 200 healthy volunteers, and one among the 48 HIV-1 infected patients. During the 354 person-years of follow-up, 860 lipopeptides injections were administered. Local reactions were common. However, in trials where lipopeptides were tested without adjuvant and appropriate diluents, none of the vaccinees experienced severe local response. Systemic reactions were generally mild and transient. No grade 4 reaction was reported; 18 subjects experienced grade 3 systemic events related to the vaccination, mainly asthenia, fever, headache and arthralgia. Multivariate analysis showed that female sex, number of injections and diluent (more reactions in 5% glucose alone than in combination with Tris-HCl buffer) significantly increased systemic reactions related to the vaccination. CONCLUSION: These data demonstrate that reactogenicity and systemic safety of HIV lipopeptides vaccine are acceptable both in healthy volunteers and HIV-infected adults.

Sustained control of viremia following therapeutic immunization in chronically HIV-1-infected individuals.

OBJECTIVE: Viral rebounds inevitably follow interruption of antiretroviral treatment in HIV-1-infected individuals. The randomized ANRS 093 aimed at investigating whether a therapeutic immunization was effective in containing the long-term viral replication following discontinuation of antiretroviral drugs in patients. METHODS: Seventy HIV-1-infected patients effectively treated with antiretroviral drugs were randomized to continue treatment alone or in combination with four boosts of ALVAC 1433 and HIV-LIPO-6T vaccines followed by three cycles of subcutaneous interleukin-2. The impact of vaccination on viral replication was assessed by interrupting antiretroviral drugs first at week 40 and thereafter during follow-up until week 100. Antiretroviral drugs were re-initiated according to predefined criteria. RESULTS: The median cumulative time (days) off treatment was greater in the vaccine group (177) than in the control group (89) (P = 0.01). The proportion of time (mean, SE) without antivirals per-patient was 42.8% (5.1) and 26.5% (4.2) in the vaccine and control groups, respectively (P = 0.005). Viremia (median log10 copies/ml), 4 weeks following the first, second and third treatment interruption was higher in control patients (4.81, 4.44, 4.53) in comparison with vaccinated patients (4.48, 4.00, 3.66) (P = 0.42, 0.015 and 0.024, respectively). HIV-specific CD4 and CD8 T-cell responses elicited by the therapeutic immunization strongly correlated with the reduction of the time of antiviral therapy (P = 0.0027 and 0.016, respectively). CONCLUSION: Our findings provide evidence that therapeutic immunization significantly impacts on HIV-1 replication. This translated into a decrease of up to 40% in the duration of exposure to antiretroviral drugs over 15 months of patients' follow-up.

Experience using MedDRA for global events coding in HIV clinical trials.

OBJECTIVES: To assess the feasibility of coding with MedDRA, the Medical Dictionary for Regulatory Activities, not only serious adverse events required for notification but also all other events usually reported in HIV clinical trials. To develop an approach for MedDRA implementation within an institutional research unit that contributes to an efficient, concise and reproducible event coding. To evaluate the impact of the maintenance and the versioning of this new medical terminology. METHODS: MedDRA versions 3.0 and 5.0 were used for coding hundreds of events reported through two HIV clinical trials. The implementation of MedDRA consisted in the setup of a training program, guidelines to clinical investigators, coding rules and medical validation process. MedDRA version 6.1 was applied to the coding made with the MedDRA version 5.0 in order to identify the assignments affected by the new version and to determine the impact of versioning. RESULTS: Coding with MedDRA all types of events in HIV clinical trials was feasible even though coders experienced some difficulties due mainly to the lack of precision in the investigator verbatim and the high specificity and sensitivity of MedDRA. The addition of appropriate tools to support the use of MedDRA improved significantly the coding of all types of events in HIV clinical trials. The impact of MedDRA versioning was limited and did not result in significant issues. The global implementation process of MedDRA required important resources in terms of qualified personnel, organisation and maintenance. CONCLUSIONS: Guidelines for investigators, coding rules and medical validation appeared to be mandatory for a successful implementation of MedDRA. The use of MedDRA, with the addition of the mentioned support tools, should ensure coding consistency and facilitate the clinical and tolerance analyses and meta-analyses in clinical trials.

Genotypic resistance analyses in nucleoside-pretreated patients failing an indinavir containing regimen: results from a randomized comparative trial: (Novavir ANRS 073).

BACKGROUND: Different studies have shown that most patients failing a first-line treatment containing a protease-inhibitor (PI) had low PI plasma levels and no PI-related resistance mutations. NOVAVIR was a randomized trial comparing stavudine/lamivudine/indinavir (d4T/3TC/IDV) and zidovudine/lamivudine/indinavir (AZT/3TC/IDV) in patients pretreated with AZT, didanosine (ddI) and/or zalcitabine (ddC) but naive for PIs. OBJECTIVE: To study the mechanisms of virological failure in NOVAVIR trial through analyses of genotypic resistance profiles of reverse transcriptase (RT) and protease (PR), and plasma IDV concentrations at time to failure. METHODS: Plasma HIV-RNA PR and RT sequences were determined in 27 failing patients (d4T/3TC/IDV n=11; AZT/3TC/IDV n=16) at baseline and at time to failure. IDV plasma measurements were performed in both samples. RESULTS: At baseline, 20 out of the 27 patients had at least two thymidine analogs associated mutations. At time to failure, mutation M184V in the RT gene was present in 22 out of the 27 failing patients. Thirteen out of the 27 (48%) patients had acquisition of PI mutations compared to baseline sequence. Of the 26 patients with adherence data, 13 (50%) subjects were classified as having difficulty in adherence. The proportion of patients with low adherence was higher in the subgroup of patients failing without acquisition of new PI mutations. CONCLUSIONS: In patients experienced with NRTIs, failure to PI-containing regimen may occur in spite of appropriate adherence to therapy and is associated with emergence of PI mutations in half of the cases. These results suggest that, although PIs have a high genetic barrier, sub-optimal activity of associated drugs may favor the selection of PI resistance mutations.

Immunological and virological efficacy of a therapeutic immunization combined with interleukin-2 in chronically HIV-1 infected patients.

OBJECTIVE: Several lines of evidence suggest that the immune system may control HIV-1 replication, but that it could fail in the long term. Strategies aimed to elicit specific immune responses may enable patients to contain virus replication. METHODS: HIV-1-infected patients were randomized to continue either their antiviral therapy alone (controls; n = 37) or with four boosts of vaccination combining ALVAC-HIV (vCP1433) and Lipo-6T vaccines (weeks 0, 4, 8, 12) followed by three cycles of subcutaneous interleukin-2 (weeks 16, 24, 32) (Vac-IL-2 group; n = 34). RESULTS: Of the Vac-IL-2 group, 15/32 (47%) exhibited a stable HIV p24 antigen-proliferative response compared with 8/33 (24%) controls (P = 0.049). After vaccination, 19/33 (58%) of the Vac-IL-2 group exhibited a multiepitopic HIV-1-specific CD4 cell proliferative response compared with 9/36 (25%) of controls (P = 0.006). The breadth and the magnitude of HIV-specific interferon-gamma-producing CD8 T cells improved in the Vac-IL-2 group. After stopping antiviral drugs, 24% of the Vac-IL-2 group lowered their viral set point compared with 5% of controls (P = 0.027). Logistic-regression analysis demonstrated that vaccine-elicited immunological responses were predictive of virological control (P = 0.046 and 0.014 for stable and multiepitopic CD4 T cell responses, respectively). CONCLUSION: This study provides proof of the concept that therapeutic immunization before antiviral drug cessation may contribute to the containment of HIV replication.

A survival method to estimate the time to occurrence of mutations: an application to thymidine analogue mutations in HIV-1-infected patients.

Virologic studies of human immunodeficiency virus type 1-infected patients have investigated either the emergence of resistance mutations according to the treatment received (type I) or their effect on subsequent regimens (type II). Type I studies provide an estimation of the frequency distribution of mutations for a given duration of therapy, but the delay to emergence of these mutations cannot be assessed. We suggest using a nonparametric estimator that generalizes the Kaplan-Meier method to data from type II studies to estimate the time to occurrence of mutations. Patients had no treatment interruption before viral genotyping. Although the curves should be interpreted with caution, they provide useful information about the kinetics of the emergence of mutations. The method was applied to the emergence of thymidine analogue mutations in patients previously treated with zidovudine (ZDV) plus didanosine or zalcitabine. Although K70R has been described as the first mutation to appear in patients receiving ZDV monotherapy, the T215Y/F mutation appeared first in patients receiving dual-nucleoside combination therapy.

Predictive factors and selection of thymidine analogue mutations by nucleoside reverse transcriptase inhibitors according to initial regimen received.

Thymidine analogue mutations were determined and compared in patients who received zidovudine monotherapy and added didanosine or zalcitabine, and in patients who started with one of these dual nucleoside combinations. Although patients who started in the era of zidovudine monotherapy had a longer duration of therapy compared with the other group, there was no statistical difference in the number of mutations between the two groups. However, thymidine analogue mutations were more frequent in patients who added didanosine to zidovudine monotherapy compared with those who added zalcitabine. Patients who started with a dual nucleoside combination developed 215Y/F first, followed by 215Y/F+41L, then 215Y/F+41L+210W, then 215Y/F+67N+70R+41L or 219Q/E, and then 215Y/F+41L+67N+70R+219Q/E. Patients who started with zidovudine monotherapy had a different pathway with the mutation at codon 70 appearing first, followed by 215Y/F+70R or 210W, then 215Y/F+41L+210W, then 215Y/F+67N+70R+219Q/E, and then 215Y/F+41L+67N+70R+210W. Medication adherence was associated with the number of mutations in both groups of patients. Two distinct mutational patterns were noted. The first pattern involved mutations at codons 41, 210 and 215, while the second involved mutations at codons 67, 70 and 219.

Effect of zidovudine resistance mutations on virologic response to treatment with zidovudine or stavudine, each in combination with lamivudine and indinavir.

The authors studied the effect of zidovudine (ZDV) resistance mutation on virologic response to treatment with ZDV or stavudine (d4T) each in combination with lamivudine and indinavir. Viral genotyping was performed on plasma HIV-1 RNA at study entry and concerned 155 patients previously treated with ZDV, didanosine, or zalcitabine and enrolled in the NOVAVIR (Agence National de Recherche sur le SIDA [ANRS] 073) trial. Three virologic responses were investigated: early response (<50 copies/mL at week 24), late response (<500 copies/mL at week 80), and virologic failure (two HIV-1 RNA >5000 copies/mL). Patients were classified as resistant or susceptible to ZDV according to the ANRS algorithm. Plasma viral RNA from 123 of 155 patients had two or more ZDV resistance mutations. The number of ZDV resistance mutations was positively correlated with the duration of prior antiviral therapy (p <.001). At week 24, 74% and 77% of patients with virus classified as resistant were responders in the d4T and ZDV arm, respectively. Similar results were found at week 80. Virologic failure was reached in 7 of 24 patients with virus classified as susceptible and in 26 of 131 patients with resistant virus (p =.29). In the ZDV arm, patients classified as resistant had longer times to virologic failure than those classified as susceptible (p =.003). In conclusion, sustained virologic response despite presence of ZDV resistance mutations implies that these mutations do not preclude an early and durable response to treatment with a potent three-drug regimen in these patients. Patients susceptible to ZDV had lower median mean corpuscular volumes and lower random indinavir levels, suggesting that adherence was the main reason for failure.

Increased risk of lipoatrophy under stavudine in HIV-1-infected patients: results of a substudy from a comparative trial.

OBJECTIVES: To compare the incidence of clinical lipodystrophy in HIV-1-infected patients receiving zidovudine or stavudine, in combination with indinavir and lamivudine, in a randomized trial. METHODS: NOVAVIR was a randomized multicentre trial comparing stavudine/lamivudine/indinavir and zidovudine/lamivudine/indinavir in 170 patients pretreated with zidovudine, didanosine or zalcitabine (> 6 months), but naive for lamivudine, stavudine and protease inhibitors. The incidence of clinical lipodystrophy and metabolic abnormalities was assessed in a subgroup of 101 patients after 30 months of follow-up. RESULTS: The incidence of lipoatrophy was increased in the stavudine arm versus the zidovudine arm, as followed: facial atrophy: 48 versus 22% of patients, P = 0.011, lower limb atrophy: 49 versus 22% of patients, P = 0.006, buttock atrophy: 47 versus 20% of patients, P = 0.009, venomegaly: 57 versus 24% of patients, P = 0.001. There was no significant difference in the incidence of clinical signs of central fat accumulation nor in fasting metabolic parameters at month 30 between the two arms. In multivariate analyses, the stavudine arm, previous therapy with didanosine, and a lower CD4 cell count at study entry were associated with an increased risk of lipoatrophy, whereas older patients and women had an increased risk of lipohypertrophy. CONCLUSION: Patients receiving stavudine/lamivudine/indinavir had a greater rate of clinical lipodystrophy, mainly lipoatrophy, than those treated with zidovudine/lamivudine/indinavir.

Adherence to antiretroviral therapy and outcomes in HIV-infected patients enrolled in an induction/maintenance randomized trial.

OBJECTIVE: To examine the effect of adherence to therapy on early virological response, later virological failure, and occurrence of adverse events in HIV-infected patients. DESIGN: A randomized trial of 3-month induction period of zidovudine/lamivudine/indinavir followed by a maintenance phase of zidovudine/lamivudine/indinavir, zidovudine/lamivudine or zidovudine/indinavir. MAIN OUTCOMES: Adherence was assessed by pill count. In the induction phase, early virological response was defined as plasma HIV-RNA<500 copies/ml at month 2 and in the maintenance phase, virological failure was defined as plasma HIV-RNA >500 copies/ml in two consecutive specimens. RESULTS: The median adherence rate was 97% in both induction (n=366) and maintenance phase (n=237). In the maintenance phase, pairwise comparisons showed a lower adherence rate in zidovudine/lamivudine/indinavir versus zidovudine/lamivudine (P=0.03), or versus zidovudine/indinavir (P=0.05). Only 13% of patients had an adherence over the maintenance phase of 80% or lower, while 40% of patients occasionally had an adherence rate of 80% or lower during this phase. Among the 362 patients with documented HIV-RNA at month 2, 86% had an early virological response. Adherence of 80% or greater was the only variable statistically predictive to early virological response (P<0.001), while baseline CD4, baseline HIV-RNA, and adherence of 95% or greater were not associated to virological response. In the maintenance phase, adherence, baseline HIV-RNA, HIV-RNA at month 3 and treatment groups were independently predictive to time to virological failure. Analysis by randomized groups indicated that difficulty in adherence (<80%) was predictive to time to failure (P<0.001) only in both indinavir-containing regimens. Occurrence of two or more severe adverse events (grade 3 and 4) was higher in patients with poor adherence although not statistically associated (P=0.12), while no association was found with minor adverse events. CONCLUSION: Adherence rate was globally lower in patients maintaining the original triple-drug therapy compared with those receiving less intensive regimens. Adherence rate was a time-dependent variable. Adherence to antiviral regimen of 80% or greater was predictive to early virological response, and adherence rate lower than 80% or 95% was predictive to virological failure, especially in indinavir-containing regimens. Occurrence of adverse events was not clearly associated to adherence.

Efficacy of zidovudine compared to stavudine, both in combination with lamivudine and indinavir, in human immunodeficiency virus-infected nucleoside-experienced patients with no prior exposure to lamivudine, stavudine, or protease inhibitors (novavir trial).

We compared the efficacy and the toxicity of zidovudine (AZT) versus stavudine (d4T), in combination with lamivudine (3TC) and indinavir, in AZT-, dideoxyinosine (ddI)-, and/or dideoxycytosine (ddC)-experienced patients in a randomized comparative multicenter trial. One hundred seventy human immunodeficiency virus type 1 (HIV-1)-infected patients, who had received AZT, ddI, and/or ddC for at least 6 months but were naive for d4T, 3TC, and protease inhibitors, were randomized to AZT at 250 to 300 mg twice daily, 3TC at 150 mg twice daily, and indinavir at 800 mg every 8 h or to d4T at 40 mg twice daily, 3TC at 150 mg twice daily, and indinavir at 800 mg every 8 h. The primary endpoint was time to virological failure, defined as plasma HIV-1 RNA levels of >5,000 copies/ml after at least 8 weeks of antiretroviral therapy. Additional endpoints were change from baseline in CD4 cell counts, AIDS-defining events and adverse events, and proportion of patients with HIV-1 RNA levels of <500 copies/ml and HIV-1 RNA levels of <50 copies/ml. At week 80, 15 patients in the AZT arm and 14 patients in the d4T arm had reached the primary endpoint, and time to virological failure did not differ between the two arms (P = 0.98). In the d4T and in the AZT arms, 67 and 73% of patients, respectively, had HIV-1 RNA levels of <500 copies/ml (P = 0.50). The median change from baseline in CD4 cell count was 195 x 10(6) and 175 x 10(6)/liter for the d4T- and AZT-containing arms, respectively. The proportions of patients with HIV-1 RNA levels of <50 copies/ml at weeks 8, 16, and 24 were similar in the two arms. The occurrence of serious adverse events was not significantly different between arms. In conclusion, in these patients heavily pretreated with AZT, switching from AZT to d4T when initiating indinavir and 3TC did not bring any additional benefit compared to maintaining AZT.